Osteoarthritis is a leading cause of disability, and a major public health issue. Progressive loss of articular cartilage due to injury and degeneration are important etiological factors in the development of osteoarthritis. While laboratory studies show a potential to reverse pathological changes in articular cartilage prior to breakdown of the articular surface, a major barrier to clinical translation of these findings is the lack of reliable clinical methods to diagnose and stage subsurface articular cartilage injury and degeneration. This translational clinical study will continue to test the central hypothesis that novel cross-sectional quantitative imaging technologies can be used clinically to improve diagnosis and staging of human articular cartilage injury and degeneration prior to breakdown of the articular surface. During the initial funding period, we completed bench to bedside clinical translational studies of two novel imaging technologies: Optical Coherence Tomography (OCT) and MRI ultrashort echo time (UTE) enhanced T2* mapping in identifying structural changes to injured and degenerating articular cartilage appearing undamaged to visual inspection. The proposed aims build logically on the clinical data and publications achieved during the initial funding period. These published and ongoing longitudinal studies show that we have the potential to validate, through continuation of this R01, 3 new imaging technologies for clinical use to (1) identify subjects with still intact cartilage that is at risk for progressive degeneration, and (2) provide in vivo metrics of subsurface injury and degeneration in human cartilage prior to surface breakdown. To achieve this, we propose the following Aims. Aim 1 will test the hypothesis intra-operative OCT detectable microstructural changes predict progressive cartilage loss as determined by changes to cartilage thickness measured on 3.0T MRI 2 and 5 years after surgery. Aim 2 will test the hypothesis that UTE-enhanced T2* (UTE-T2*) map values predict cartilage injury and degeneration as assessed by conventional arthroscopy. Aim 3 will test the hypothesis that changes in quantitative MRI T2 relaxation times six months after surgery predict cartilage loss as determined by morphometric MRI measurements 2 years after surgery. The proposed Aims will be achieved using the same two carefully selected populations of individuals who do not yet have osteoarthritis but are at high risk for progressive cartilage degeneration studied previously: (1) the pre- osteoarthritic degenerative meniscus tear (DMT) cohort and (2) the post-joint injury anterior cruciate ligament tear (ACLT) cohort. Achieving the aims will provide new quantitative clinical diagnostic tools to support a clinical paradigm shift towards treatment of cartilage injury and degeneration years before what is currently possible. Potential advantages of earlier treatment include the possibility of delaying or preventing the onset of disabling osteoarthritis.